TY - JOUR
T1 - A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin
AU - Shaili, Evyenia
AU - Fernández-Giménez, Marta
AU - Rodríguez-Astor, Savina
AU - Gandioso, Albert
AU - Sandín, Lluís
AU - García-Vélez, Carlos
AU - Massaguer, Anna
AU - Clarkson, Guy J.
AU - Woods, Julie A.
AU - Sadler, Peter J.
AU - Marchán, Vicente
N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/12/7
Y1 - 2015/12/7
N2 - A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.
AB - A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.
KW - Antineoplastic Agents
KW - Cell Line, Tumor
KW - Guanidine
KW - Humans
KW - Ligands
KW - Organoplatinum Compounds
KW - RNA
U2 - 10.1002/chem.201502373
DO - 10.1002/chem.201502373
M3 - Article
C2 - 26662220
SN - 0947-6539
VL - 21
SP - 18474
EP - 18486
JO - Chemistry: a European Journal
JF - Chemistry: a European Journal
IS - 50
ER -